The RAS/RAF/MEK/ERK pathway is activated in more than 30% of human cancers, most commonly via mutation in the K-ras oncogene and also via mutations in BRAF. The pathway has therefore attracted significant interest as a therapeutic target or cancer (P. J. Roberts and C. J. Der, Oncogene 2007 26:3291-310)). Efforts to target RAS directly have not been successful to date, but recent clinical trials with BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors have suggested targeting these downstream RAS effectors holds promise in the treatment of cancers harboring oncogenic mutations in the pathway (K. T. Flaherty et al., Curr. Opin. Oncol. 2010 22:178-83). Although clinical responses and antitumor activity can be impressive, particularly for BRAF inhibitors in BRAF mutant melanoma, the majority of patients ultimately develop clinical resistance and progressive disease (Flaherty, supra; D. B. Solit and N. Rosen, N. Engl. J. Med. 2011 364:772-4). Preclinical studies have identified multiple mechanisms of acquired resistance to BRAF inhibitors, including, switching between RAF isoforms (J. Villaneuva et al., Cancer Cell 2010 18:683-95), upregulation of RTK or NRAS signaling (R. Nazarian et al., Nature 2010 468:973-7), and reactivation of mitogen-activated kinase (MAPK) signaling via COT activation (C. M. Johannessen et al., Nature 2010 468:968-72) or a MEK kinase activating mutation (N. Wagle et al., J. Clin. Oncol. 2011 29:3085-96). Similarly preclinical studies have identified distinct mechanisms by which cell acquires resistance to MEK inhibition, including amplification of mutant BRAF (R. B. Corcorran et al., Sci. Signal 2011 3:ra84), STAT3 upregulation (B. Dai et al., Cancer Res. 2011 71:3658-68), or mutations in the allosteric pocket of MEK that can directly binding of inhibitors to the MEK kinase activity (H. Wang et al., Cancer Res. 2011 71:5535-45; C. M. Emery et al., Proc. Nat. Acad. Sci. USA 2009 106:20411-6). MEK mutations have been described in tumors samples from patients treated with MEK (Emera, supra) or BRAF (Wagle supra) inhibitors, showing clinical relevance.
While selective ERK1/2 inhibitors have been reported and are current in clinical development, in comparison with RAF and MEK inhibitors, the identification and development of small molecule inhibitors against ERK1/2 that act directly downstream of MEK, has lagged behind.